WAKE FOREST JOURNAL OF BUSINESS AND INTELLECTUAL PROPERTY LAW 2 2 "2 2! !2 2 2 THE VALIDITY CHALLENGE TO COMPOUND CLAIMS AND THE (UN?)PREDICTABILITY OF CHEMICAL ARTS † Guyan Liang, Ph.D., J.D. I. INTRODUCTION ............................................................... 40 II. HATCH-WAXMAN ACT AND GENERIC DRUGS ............. 41 III. THE GENERAL PRINCIPLE OF OBVIOUSNESS ANALYSYS .......................................................................... 44 IV. THE DEVELOPMENT OF THE LEAD COMPOUND THEORY ............................................................................. 47 A.THE HASS-HENZE DOCTRINE ...................................... 47 B.THE MODERN OBVIOUSNESS ANALYSIS FOR CHEMICAL COMPOUNDS ............................................... 49 C.THE LEAD COMPOUND THEORY FOR OBVIOUSNESS ANALYSIS OF CHEMICAL ARTS ..................................... 52 V. RECENT CACF CASES APPLYING THE LEAD COMPOUND THEORY ........................................................ 54 A.ELI LILLY V. ZENITH GOLDLINE ................................... 54 B.TAKEDA V. ALPHAPHARM ............................................. 57 C.EISAI V. DR. REDDY’S LAB ........................................... 59 D.PROCTER & GAMBLE V. TEVA ...................................... 62 E.ALTANA PHARMA V. TEVA ............................................ 63 F. DAIICHI V. MATRIX LABS .............................................. 65 G.OTSUKA V. SANDOZ ....................................................... 67 VI. THE PREDICTABILIY OF CHEMICAL COMPOUNDS .... 69 A.SOME PROPERTIES OF CHEMICAL COMPOUNDS † Associate, Budd Larner, P.C.; Advisory board member, Center for Drug Design, Mercer University College of Pharmacy and Health Sciences. Prior to his legal career, the author worked as a research scientist in drug discovery for fifteen years. The views expressed herein are the personal views of the author and do not necessarily reflect those of Budd Larner or any other organizations with which the author was affiliated. The author would like to thank Mr. Andrew Miller for his support. The author also would like to acknowledge Professor Jordan Paradise for her critical review of the manuscript and insightful comments. 2! !/2 .2,+- 22 "(2 2/ CAN BE PREDICTED BASED ON PHYSICAL CHEMICAL PRINCIPLES ................................................. 69 B.SOME PROPERTIES OF CHEMICAL COMPOUNDS CAN BE PREDICTED THROUGH SARS ........................... 74 C.THE MOST DESIRABLE COMPOUND MAY ALSO BE IDENTIFIED THROUGH AN EXHAUSTIVE SEARCH OF A FINITE NUMBER OF POSSIBLE SOLUTIONS ................. 76 D.THE OBVIOUSNESS ANALYSIS BASED ON THE LEAD COMPOUND THEORY SHOULD REFLECT THE (UN?)PREDICTABILITY OF CHEMICAL COMPOUNDS ..... 79 VII. CONCLUSION ............................................................... 80 2#2 22 *2 . *2 "2 *2)2 *2*2 * I. INTRODUCTION Pharmaceutical research and development (“R&D”) is a lengthy and expensive endeavor with a possibility of high return, yet a low probability of success. In 2006, 105 drugs had annual sales of more than one billion US dollars, and the best-selling drug, Lipitor® from Pfizer, topped off at nearly $14 billion.1 Developing a drug, however, takes from ten to fifteen years with an average cost around $1.3 billion. 2 For every 5,000 to 10,000 compounds investigated in medicinal chemistry, about 250 may progress into preclinical evaluation, five of which may enter clinical studies, and one lucky compound may eventually receive approval for marketing from the United States Food and Drug Administration (the “FDA”).3 Whether pharmaceutical companies that invest in drug discovery can recover their investment depends heavily on the patent protection of their drugs. If the patent expires or is declared invalid, the price of a drug decreases significantly under generic competition. 4 The validity of those patent claims, especially compound claims, often is the subject of fierce litigation, the resolution of which may impact billions of dollars of business revenue. Often, the validity challenge to a compound claim is based on the theory that the claimed invention was obvious in light of the prior art available at the time of the invention to a person having ordinary skill in the art. While the general principle of obviousness analysis applies to chemical compound claims, the courts have also developed a special analysis for chemical compound cases because of the perceived unpredictability of the chemical art.5 However, as will be discussed in this article, this assumption may not always be true and should not be treated as it is. Part II of this article will discuss the Hatch-Waxman Act, which 1 Andrew Humphreys, Med Ad News 200 world's best-selling medicines, MED AD NEWS (July 1, 2007), available at http://business.highbeam.com/437048/article- 1G1-167388387/med-ad-news-200-world-bestselling-medicines-lipitor. 2 Pharmaceutical Industry Profile 2011, PHARM. RES. & MFRS. OF AM., 10, 12 (April 2011), available at http://www.phrma.org/sites/default/files/159/phrma_profile_2011_final.pdf. 3 Id. 4 Frank R. Lichtenberg & Gautier Duflos, Time release: The Effect of Patent Expiration on U.S. Drug Prices, Marketing, and Utilization by the Public, MANHATTAN INST. FOR POL’Y RES. (October 2009), http://www.manhattan- institute.org/html/mpr_11.htm (stating that between twelve and sixteen years after launching, the average generics’ mean market share increases from eight percent to sixty-five percent while the mean price declines forty-four percent). 5 See In re Dillon, 919 F.2d 688, 698 (Fed. Cir. 1990). 2! !/2 .2,+- 22 # 2 2/ was introduced in 1984 and created the generic drug pathway to the market. Within this framework, the validity of drug patents are often challenged based on various theories including that the claimed invention was obvious to a person skilled in the art. Part III will discuss the general legal principle of the obviousness analysis under the context of patent validity, including the impact of KSR v. Teleflex (“KSR”).6 Part IV will discuss the evolution of obviousness analysis for chemical compound claims, leading toward the development of the modern lead compound theory. Part V will survey applications of the lead compound theory in the Court of Appeals for the Federal Circuit (the “CAFC”) since 2006 and discuss the teachings of each case. As will be discussed in more detail, the lead compound theory and those decisions applying the lead compound theory are largely based on the presumption that properties of chemical arts are unpredictable and that a small change in chemical structure may cause a significant variation in properties. Therefore, according to the CAFC, structural similarity alone does not suffice to establish a prima facie case of obviousness. As will be discussed in Part VI, however, this is not always true. Many strategies and approaches used in modern drug discovery, such as structure activity relationship (“SAR”) analysis in medicinal chemistry and rational drug design, can be used to predict properties of chemical compounds. It should be recognized by the courts that properties of chemical arts are not always unpredictable and that a properly validated prediction can contribute to the obviousness analysis in patent validity litigation. II. HATCH-WAXMAN ACT AND GENERIC DRUGS The pharmaceutical industry is a heavily regulated industry, and a new drug cannot be marketed in this country without approval by the FDA.7 If the innovator company believes that its newly-discovered compound can be used to treat certain diseases, it may sponsor clinical trials of the drug by filing an Investigational New Drug Application (“IND”) with the FDA, which includes a summary of animal pharmacology and toxicity studies, chemistry and manufacturing information, and proposed clinical protocols.8 If the FDA does not object to the IND within thirty days, the innovator company may start 6 KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007). 7 See 21 U.S.C. § 321 (2006); see also Patricia I. Carter, Federal Regulation of Pharmaceuticals in the United States and Canada, 21 LOY. L.A. INT’L & COMP. L.J. 215, 229 (May 1999). 8 See Carter, supra note 7, at 231. 2#!2 22 *2 . *2 "2 *2)2 *2*2 * the clinical trials outlined in the IND.9 After all clinical trials have been completed and all data have been analyzed, the innovator company may file a New Drug Application (“NDA”), outlining the route of administration, dosage, intended use, labeling, etc.10 Once the FDA approves the NDA, the innovator company may market the new drug in the United States.11 The innovator company, having invested heavily in the preclinical research, clinical trials, and approval process of the new drug, is entitled to an exclusive marketing right that is guaranteed by both patent law and the FDA data exclusivity provision, whichever is longer.12 As a patent holder, the innovator company has a right to exclude others from practicing the patented invention in the United States within the term of the patent, which is seventeen years from the date of issuance for patents filed on or before June 8, 1995, or twenty years from the date of filing for patents filed after that date.13 A patent term extension is available to compensate the patent holder for delays in the patent review and FDA approval processes if the patent holder acted with due diligence during the period.14 Parallel to the patent protection, the innovator company is also entitled to a five-year period of data exclusivity from the date of FDA approval if the new drug product contains a New Chemical